A Murine Model for Human ECO Syndrome Reveals a Critical Role of Intestinal Cell Kinase in Skeletal Development

ABSTRACT Morphogenetic conversions contribute to the pathogenesis of Candida albicans invasive infections. Many studies to date have convincingly demonstrated a link between filamentation and virulence; however, relatively little is known regarding the role of the filament-to-yeast transition during the pathogenesis of invasive candidiasis. We previously identified the C. albicans pescadillo homolog ( PES1 ) as essential during yeast growth and growth of lateral yeast on hyphae but not during hyphal growth. Furthermore, we demonstrated that PES1 is required for virulence in vivo in a Galleria mellonella larva model of candidiasis. Here, we have used a regulatable tetO-PES1 / pes1 strain to assess the contribution of C. albicans PES1 to pathogenesis in the commonly used and clinically relevant murine model of hematogenously disseminated candidiasis. Our results indicate that a physiologically controlled level of PES1 expression is required for full virulence in this animal model, with virulence defects observed both when PES1 is overexpressed and and when it is depleted. The pathogenetic defect of cells depleted of PES1 is not due to a general growth defect, as demonstrated by the fact that PES1 -depleted cells still kill Caenorhabditis elegans as efficiently as the wild type due to hyphal outgrowth through worm tissues. Our results suggest a critical role of lateral yeast growth in the ability of C. albicans to normally proliferate within tissues, as well as a pivotal role for Pes1 in the normal developmental cycle of C. albicans within the mammalian host during infection.

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Critical role of CD23 in allergen-induced bronchoconstriction in a murine model of allergic asthma

European Journal of Immunology ◽

10.1002/(sici)1521-4141(199909)29:09<2957::aid-immu2957>3.0.co;2-4 ◽

1999 ◽

Vol 29 (9) ◽

pp. 2957-2967 ◽

Cited By ~ 26

Author(s):

Gorana Dasic ◽

Pierre Juillard ◽

Pierre Graber ◽

Suzanne Herren ◽

Tony Angell ◽

...

Keyword(s):

Allergic Asthma ◽

Murine Model ◽

Critical Role

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Role of RUNX2 in Melanoma: A New Player in Tumor Progression and Resistance to Therapy

10.5772/intechopen.97105 ◽

2021 ◽

Author(s):

Rachael Pulica ◽

Cohen Solal Karine ◽

Ahmed Lasfar

Keyword(s):

Osteoblast Differentiation ◽

Skeletal Development ◽

Critical Role ◽

Invasion And Metastasis ◽

Braf Mutations ◽

Mesenchymal Progenitors ◽

Oncogenic Pathways ◽

Cancer Types ◽

Braf Mutant

RUNX2, a transcription factor, initially known for its indispensable role in skeletal development. RUNX2 is essential for osteoblast differentiation and the maintain of the osteocyte balance. RUNX2 acts directly on osteoblasts via Fgf pathway or on mesenchymal progenitors through Hedgehog, Wnt, Pthlh and DLX5. Currently, many reports point its critical role in the progression and metastasis of several cancer types. RUNX2 is involved in EMT process, invasion and metastasis through the modulation of important oncogenic pathways, including Wnt, FAK/PTK and AKT. In melanoma, RUNX2 is a key player in mediating intrinsic RTK-associated pro-oncogenic properties. We have showed a dramatic up regulation of RUNX2 expression with concomitant up-regulation of EGFR, IGF-1R and AXL, in melanoma cells rendered resistant to BRAF mutant inhibitors. Approximately half of melanomas carry BRAF mutations which enhance tumor invasion and metastasis. In this chapter, we describe the potential mechanisms, leading to the upregulation of RUNX2 in melanoma with BRAF mutations. We also highlight the critical role of PI3K/AKT in the expression and activation of RUNX2, and its consequences on the regulation of many critical factors, controlling cancer invasion and metastasis.

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Critical Role of Zinc in a New Murine Model of EnterotoxigenicEscherichia coliDiarrhea

Infection and Immunity ◽

10.1128/iai.00183-18 ◽

2018 ◽

Vol 86 (7) ◽

pp. e00183-18 ◽

Cited By ~ 11

Author(s):

D. T. Bolick ◽

P. H. Q. S. Medeiros ◽

S. E. Ledwaba ◽

A. A. M. Lima ◽

J. P. Nataro ◽

...

Keyword(s):

Murine Model ◽

Intestinal Inflammation ◽

Inflammatory Responses ◽

Critical Role ◽

Disease Onset ◽

Watery Diarrhea ◽

Content Type ◽

Heat Stable

ABSTRACTEnterotoxigenicEscherichia coli(ETEC) is a major cause of traveler's diarrhea as well as of endemic diarrhea and stunting in children in developing areas. However, a small-mammal model has been badly needed to better understand and assess mechanisms, vaccines, and interventions. We report a murine model of ETEC diarrhea, weight loss, and enteropathy and investigate the role of zinc in the outcomes. ETEC strains producing heat-labile toxins (LT) and heat-stable toxins (ST) that were given to weaned C57BL/6 mice after antibiotic disruption of normal microbiota caused growth impairment, watery diarrhea, heavy stool shedding, and mild to moderate intestinal inflammation, the latter being worse with zinc deficiency. Zinc treatment promoted growth in zinc-deficient infected mice, and subinhibitory levels of zinc reduced expression of ETEC virulence genescfa1,cexE,sta2, anddegPbut not ofeltA in vitro. Zinc supplementation increased shedding and the ileal burden of wild-type (WT) ETEC but decreased shedding and the tissue burden of LT knockout (LTKO) ETEC. LTKO ETEC-infected mice had delayed disease onset and also had less inflammation by fecal myeloperoxidase (MPO) assessment. These findings provide a new murine model of ETEC infection that can help elucidate mechanisms of growth, diarrhea, and inflammatory responses as well as potential vaccines and interventions.

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Whole Genome Sequencing Indicates Heterogeneity of Hyperostotic Disorders in Dogs

Genes ◽

10.3390/genes11020163 ◽

2020 ◽

Vol 11 (2) ◽

pp. 163 ◽

Cited By ~ 1

Author(s):

Anna Letko ◽

Fabienne Leuthard ◽

Vidhya Jagannathan ◽

Daniele Corlazzoli ◽

Kaspar Matiasek ◽

...

Keyword(s):

Skeletal Development ◽

Critical Role ◽

Exon Skipping ◽

Missense Variant ◽

Whole Genome ◽

Col1a1 Gene ◽

Locus Heterogeneity ◽

Cortical Hyperostosis ◽

Neoplastic Disorders

Craniomandibular osteopathy (CMO) and calvarial hyperostotic syndrome (CHS) are proliferative, non-neoplastic disorders affecting the skull bones in young dogs. Different forms of these hyperostotic disorders have been described in many dog breeds. However, an incompletely dominant causative variant for CMO affecting splicing of SLC37A2 has been reported so far only in three Terrier breeds. The purpose of this study was to identify further possible causative genetic variants associated with CHS in an American Staffordshire Terrier, as well as CMO in seven affected dogs of different breeds. We investigated their whole-genome sequences (WGS) and filtered variants using 584 unrelated genomes, which revealed no variants shared across all affected dogs. However, filtering for private variants of each case separately yielded plausible dominantly inherited candidate variants in three of the eight cases. In an Australian Terrier, a heterozygous missense variant in the COL1A1 gene (c.1786G>A; p.(Val596Ile)) was discovered. A pathogenic missense variant in COL1A1 was previously reported in humans with infantile cortical hyperostosis, or Caffey disease, resembling canine CMO. Furthermore, in a Basset Hound, a heterozygous most likely pathogenic splice site variant was found in SLC37A2 (c.1446+1G>A), predicted to lead to exon skipping as shown before in SLC37A2-associated canine CMO of Terriers. Lastly, in a Weimaraner, a heterozygous frameshift variant in SLC35D1 (c.1021_1024delTCAG; p.(Ser341ArgfsTer22)) might cause CMO due to the critical role of SLC35D1 in chondrogenesis and skeletal development. Our study indicates allelic and locus heterogeneity for canine CMO and illustrates the current possibilities and limitations of WGS-based precision medicine in dogs.

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Deletion at an 1q24 locus reveals a critical role of long noncoding RNA DNM3OS in skeletal development

10.21203/rs.3.rs-93462/v1 ◽

2020 ◽

Author(s):

Ting-ting Yu ◽

Qiu-fan Xu ◽

Hui-jie Huang ◽

Sarah Dugan ◽

Lei Shao ◽

...

Keyword(s):

Noncoding Rna ◽

Endochondral Ossification ◽

Bone Growth ◽

Skeletal Development ◽

Critical Role ◽

Chondrocyte Proliferation ◽

Complex Processes ◽

Opposite Strand ◽

Non Coding Rnas

Abstract Background: Skeletal development and maintenance are complex processes known to be coordinated by multiple genetic and epigenetic signaling pathways. However, the role of long non-coding RNAs (lncRNAs), a class of crucial epigenetic regulatory molecules, has been under explored in skeletal biology. Results: Here we report a young patient with short stature, hypothalamic dysfunction and mild macrocephaly, who carries a maternally inherited 690kb deletion at Chr.1q24.2 encompassing a noncoding RNA gene, DNM3OS, embedded on the opposite strand in an intron of the DYNAMIN 3 (DNM3)gene. We show that lncRNA DNM3OS sustains the proliferation of chondrocytes independent of two co-cistronic microRNAs miR-199a and miR-214. We further show that nerve growth factor (NGF), a known factor of chondrocyte growth, is a key target of DNM3OS-mediated control of chondrocyte proliferation.Conclusion: This work demonstrates that DNM3OS is essential for preventing premature differentiation of chondrocytes required for bone growth through endochondral ossification.

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Intestinal cell kinase regulates chondrocyte proliferation and maturation during skeletal development

10.1101/139089 ◽

2017 ◽

Author(s):

Mengmeng Ding ◽

Li Jin ◽

Lin Xie ◽

So Hyun Park ◽

Yixin Tong ◽

...

Keyword(s):

Intervertebral Disc ◽

Molecular Mechanisms ◽

Skeletal Development ◽

Spinal Column ◽

Intestinal Cell ◽

Long Bones ◽

Chondrocyte Proliferation ◽

Kinase Gene ◽

Skeletal Defects ◽

Intestinal Cell Kinase

AbstractAn autosomal recessive loss-of-function mutation R272Q in human ICK (intestinal cell kinase) gene causes profound multiplex developmental defects in human ECO (endocrine-cerebro-osteodysplasia) syndrome. ECO patients exhibit a wide variety of skeletal abnormalities, yet the underlying cellular and molecular mechanisms by which ICK regulates skeletal development remain largely unknown. The goal of this study is to understand the structural and mechanistic basis underlying skeletal anomalies caused by ICK dysfunction. Ick R272Q knock in transgenic mouse model not only recapitulated major ECO skeletal defects such as short limbs and polydactyly but also revealed a deformed spine with deficient intervertebral disc. Loss of ICK functions markedly reduces mineralization in the spinal column, ribs, and long bones. Ick mutants show a significant decrease in the number of proliferating chondrocytes and type X collagen-expressing hypertrophic chondrocytes in the spinal column and the growth plate of long bones. Our results demonstrate that ICK plays an important role in bone and intervertebral disc development by promoting chondrocyte proliferation and maturation, and thus provide novel mechanistic insights into the skeletal phenotypes of human ECO syndrome.

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